Strain-Based Design, Direct Macrocyclization, and Metal Complexation of Thiazole-Containing Calix[3]pyrrole Analogues

Coordination chemistry of ring-contracted porphyrins, such as subporphyrin and calix[3]pyrrole, has been largely unexplored due to the synthetic difficulty of their free-base analogues. Here, we report strain-based molecular design and high yield synthesis of thiazole-containing calix[3]pyrrole analogues for metal complexation. The AFIR method and StrainViz analysis were used to perform a conformational search and evaluate/visualize ring strain, respectively. The results indicated that thiazole-containing analogues are less strained than the parent calix[3]pyrrole, while incorporation of imidazole or oxazole unexpectedly leads to an increase in total strain. In fact, calix[1]furan[2]thiazole was obtained in 60% yield by direct macrocyclization between α-bromoketone and bis(thioamide), whereas meso-N(sp2)-bridged analogue, which was calculated to be more strained by 5.1 kcal/mol, was obtained only in a 2% yield. Calix[1]furan[2]thiazole was converted to calix[1]pyrrole[2]thiazole for investigation of metal complexation. Through reaction with Et2Zn, calix[1]pyrrole[2]thiazole bound a Zn(II) ion in a tridentate fashion adopting a cone conformation, furnishing water/air stable organozinc complex that catalyzes polymerization of lactide. Whereas, Ag(I) and Pd(II) ions were chelated by partial cone conformation of calix[1]pyrrole[2]thiazole in a bidentate fashion. Strain-based molecular design has expanded the synthetic access to contracted porphyrinoids and opened up the opportunity of their rich coordination chemistry.